Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

Ziv, Omer; Zeisel, Amit; Mirlas-Neisberg, Nataly; Swain, Umakanta; Nevo, Reinat; Ben-Chetrit, Nir; Martelli, Maria Paola; Rossi, Roberta; Schießer, Stefan; Canman, Christine E.; Carell, Thomas; Geacintov, Nicholas E.; Falini, Brunangelo; Domany, Eytan; Livneh, Zvi

doi:10.1038/ncomms6437

Cited by 51 publications

(42 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another potential function of pol h in cancer cells could be the error-free or error-prone bypass of various DNA lesions. It was suggested in a recent paper 53 that NPM1 (nucleophosmin) regulates translesion DNA synthesis (TLS) via an interaction with the catalytic core of pol h. NPM1 deficiency causes a TLS defect due to the proteasomal degradation of pol h. The prevalent NPM1 mutation (c+) leading in one-third of AML patients to NPM1 mislocalization results in a loss of pol h, which may explain why no significant excess of mutation in pol h motifs was found for acute myeloid leukemia ( Table 2). These results hint at the complexity of regulation of pol h in cancer cells and provide an explanation of why pol h mutational signatures are found only in some cancer types/subtypes.…”

Section: Discussionmentioning

confidence: 96%

DNA polymerase η mutational signatures are found in a variety of different types of cancer

et al. 2018

View full text Add to dashboard Cite

DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.

show abstract

Section: Discussionmentioning

confidence: 96%

DNA polymerase η mutational signatures are found in a variety of different types of cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…TLS is a mechanism by which damaged DNA is bypassed by low fidelity polymerases. NPM1 stabilizes one of these polymerases, polymerase ?, protecting it from degradation until it is needed for TLS 113 . Thus NPM1 maintains functional roles in multiple DNA damage response pathways, including BER, NER, and TLS.…”

Section: Functional Roles For Nucleolar Proteins In Dna Repairmentioning

confidence: 99%

Crosstalk between the nucleolus and the DNA damage response

Ogawa

Baserga

2017

Mol. BioSyst.

View full text Add to dashboard Cite

Nucleolar function and the cellular response to DNA damage have long been studied as distinct disciplines. New research and a new appreciation for proteins holding multiple functional roles, however, is beginning to change the way we think about the crosstalk among distinct cellular processes. Here, we focus on the crosstalk between the DNA damage response and the nucleolus, including a comprehensive review of the literature that reveals a role for conventional DNA repair proteins in ribosome biogenesis, and conversely, ribosome biogenesis proteins in DNA repair. Furthermore, with recent advances in nucleolar proteomics and a growing list of proteins that localize to the nucleolus, it is likely that we will continue to identify new DNA repair proteins with a nucleolar-specific role. Given the importance of ribosome biogenesis and DNA repair in essential cellular processes and the role that they play in diverse pathologies, continued elucidation of the overlap between these two disciplines will be essential to the advancement of both fields and to the development of novel therapeutics.

show abstract

“…NPM1 is involved in many and different cellular functions which have been extensively reviewed recently [5, 6, 7]. Among them NPM1 plays a role in: i) rRNA expression and maturation [8, 9], ii) ribosome assembly and export [10, 11], iii) centrosome duplication [12, 13], iv) DNA replication, recombination, transcription, and repair [1, 5, 6, 14, 15], v) molecular chaperoning for histones and other proteins [5, 16, 17, 18]. Many of these functions are fulfilled through the interaction with different protein partners and indeed NPM1 has been reported to interact with a plethora of proteins [reviewed in 6].…”

Section: Introductionmentioning

confidence: 99%

Molecules that target nucleophosmin for cancer treatment: an update

et al. 2016

View full text Add to dashboard Cite

Nucleophosmin is a highly and ubiquitously expressed protein, mainly localized in nucleoli but able to shuttle between nucleus and cytoplasm. Nucleophosmin plays crucial roles in ribosome maturation and export, centrosome duplication, cell cycle progression, histone assembly and response to a variety of stress stimuli. Much interest in this protein has arisen in the past ten years, since the discovery of heterozygous mutations in the terminal exon of the NPM1 gene, which are the most frequent genetic alteration in acute myeloid leukemia. Nucleophosmin is also frequently overexpressed in solid tumours and, in many cases, its overexpression correlates with mitotic index and metastatization. Therefore it is considered as a promising target for the treatment of both haematologic and solid malignancies. NPM1 targeting molecules may suppress different functions of the protein, interfere with its subcellular localization, with its oligomerization properties or drive its degradation. In the recent years, several such molecules have been described and here we review what is currently known about them, their interaction with nucleophosmin and the mechanistic basis of their toxicity. Collectively, these molecules exemplify a number of different strategies that can be adopted to target nucleophosmin and we summarize them at the end of the review.

show abstract

Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin

Cited by 51 publications

References 69 publications

DNA polymerase η mutational signatures are found in a variety of different types of cancer

DNA polymerase η mutational signatures are found in a variety of different types of cancer

Crosstalk between the nucleolus and the DNA damage response

Molecules that target nucleophosmin for cancer treatment: an update

Contact Info

Product

Resources

About